ME00606B - A process for the preparation of n,n'-bis[2, 3-dihydroxypropyl] -5-[ (hydroxyacetyl) methylamino]-2, 4,6-triiodo-1, 3-benzenedi carboxamide - Google Patents

Abstract

A New Process for the Preparation of N, N'-Bis [2,3-Dihydroxypropyl] -5- [(hydroxyacetyl) methylamino] -2,4,6-triodo-1,3-benzenedicarboxamideformula (I) commonly known as Iomeprol, a novel non- The ionic contrast agent exhibits very good security and effective contrast.

Description

The present invention relates to new processes for the preparation of N,N'-bis[2,3-dihydroxypropyl]-5-[(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarboxamide of formula (I) , commonly known as Iomeprol, a new non-ionic contrast agent that demonstrates excellent safety and effective contrast.

The synthesis of compounds of formula (I) was first described in EP 26,281, but the following EP 365,541 suggested a different synthesis route, based on the Smiles rearrangement reaction of 5-Alkoxy-2,4,6-triiodo-1,3-benzenedicarboxamide derivatives under basic aqueous conditions to give the corresponding 5-(hydroxyacyl)amino derivatives, according to Scheme 1 (see below).

The advantages of this second synthesis over the one described in EP 26,281 mainly stem from the avoidance of some reagents and solvents such as: thionyl chloride, acetic anhydride, methyl iodide, methylene chloride and chloroform, as well as reactions (such as catalytic reduction with hydrogen), which are environmentally and toxicologically dangerous in the conditions of industrial production and therefore require special operating conditions.

The key intermediate of the synthetic pathway is the compound of formula (VII), which is synthesized as described in EP 185,130 and outlined in Scheme 1. (see page 2)

The process involves the use of 5-hydroxy-1,3-benzenedicarboxylic acid as the starting compound, which is esterified under usual conditions with MeOH and acid catalysis to the methyl diester of formula (II). The latter is hot amidified with 1-amino-2,3-propanediol (commonly named isoserinol), with 100% reagent in excess. The methanol formed during the reaction is distilled and the excess amine is removed using strong cationic resins to give the compound of formula (III). The resulting diamide is iodinated in an aqueous basic solution with a 2.5M KICl2 solution to give the compound of formula (IV).

No details are given considering the conditions for recovering compound (IV) which is transformed into the corresponding sodium salt (V) and then reacted while hot with methyl bromoacetate in dimethylacetamide to give, after recrystallization from methanol, the compound of formula (VI), which is subject to amidation with hot methylamine to produce compound (VII). EP 185,130 discloses compound (VII) as an intermediate for the synthesis of a number of contrast agents derived from N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-hydroxy-1,3-benzenedicarboxylic acid amide.

However, weighing this procedure shows unexpected technical problems, in short:

- in the formation of the dimethyl ester of formula (II), as is well known in the literature, due to the characteristics of methanol, a non-catalytic amount of H2SO4 is required to shift the equilibrium towards the formation of the ester. Under these conditions, monomethyl sulfate is formed as a side product which, analogous to the well-known dimethyl sulfate, is dangerous for health;

- the compound (IV), as well as the sodium salt of the formula (V), must be isolated from the aqueous solution;

- alkylation of compound (V) with methyl bromoacetate must be carried out in dimethylacetamide, which must be recycled for economic reasons;

- compound (VI) must be purified by crystallization from methanol;

- in the described iodination conditions, iodine must be used in excess, to the detriment of the next synthetic step, in such a way that the excess can act as an oxidant in relation to the alcohol group present in the amides at the 3- and 5-positions to obtain the following compound

which is difficult to separate from compound (IV) and which, after successive synthetic steps, produces an impurity that contaminates the final product, Iomeprol. This impurity is significantly toxic and its formation must therefore be prevented as much as possible.

A safe alternative procedure for the preparation of (VII) was sought, with the aim of making the industrial synthesis much more environmentally safe, avoiding the use of organic solvents as much as possible, while preventing the formation of by-products hazardous to health.

Therefore, the object of the present invention is a new process for the preparation of Iomeprol, comprising the steps shown in the following Scheme 2:

esterification with butanol and acid catalysis to give 5-hydroxy-1,3-benzenedicarboxylic acid butyl diester (VIII);

a) amidation of compound (VIII) with excess isoserinol to obtain an aqueous solution of N,N'-bis-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzene-dicarboxamide (III);

b) iodination of compound (III) with ICl, in stoichiometric amounts or in an excess of 1%, to obtain N,N'-bis-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodo- 1,3-benzenedicarboxamide (IV);

c) alkylation of compound (IV) with compound (IX), 2-chloro-N-methyl-acetamide in aqueous solution to give N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo- 5-[2-(methylamino)-2-oxoethoxy]-1,3-benzene-dicarboxamide (VII), which is used as a wet product; finally,

d) Smiles rearrangement of compound (VII) under basic conditions and successive reduction to give Iomeprole (I).

A further object of the present invention is a process for the preparation of compound (VII), a useful intermediate for the preparation of an iodinated contrast agent as described in EP 185,130, comprising steps a), b), c) and d) and further final drying (VII).

Contrary to what is disclosed in EP 185,130, the process of the present invention is characterized in that all synthetic steps b) to e), including the preparation of the alkylating agent of formula (IX), are carried out in aqueous solution, and that organic solvents are avoided and that that the recovery of individual intermediates is no longer necessary, but it is possible to work continuously directly in solutions of the intermediates themselves.

In step a), the formation of the butyl diester of formula (VIII) enables the previously mentioned problems to be successfully overcome. In fact, if carried out according to the methods of the invention, it is possible to use a catalytic amount of H 2 SO 4 , which preferably corresponds to 6% per mole of 5-hydroxy-1,3-benzenedicarboxylic acid.

Alternatively, a catalytic amount of p-toluenesulfonic acid monohydrate may be used, preferably in amounts equivalent to 6% per mole of 5-hydroxy-1,3-benzenedicarboxylic acid. The esterification reaction can also be carried out at heat and under gradually decreasing pressure, instead of at atmospheric pressure.

Compound (VIII) can be recovered either by direct crystallization from the final reaction mixture, previously concentrated, or by precipitation from an alkaline aqueous solution, with prior elimination of the organic solvent. In the first case, the final crystallization is carried out cold (T of about 5oC) and most of the yield must be recovered through repeated concentration of the mother liquors, or the mother liquors of the first yield must be recycled and used in successive esterification reactions. In the second case (reproduction from an alkaline aqueous solution) the reaction mixture is concentrated into a precipitate, which is successively treated with an aqueous solution of an inorganic base (preferably sodium or potassium hydroxide or ammonia): by controlled cooling of the resulting emulsion, compound (VIII) is obtained as a partially solid crystal. Compound (VIII) can be filtered or centrifuged or filter-pressed and dried.

Alternatively, compound (VIII) can be redissolved in n-butanol and the resulting solution can be used in the next step b). The advantages of direct use of the solution are:

- the possibility to avoid the step of recovering the wet product,

- to avoid the drying step, which requires prolonged treatment in a static dryer under vacuum at 30-40oC,

-compound (II) is a solid with a low melting point.

Step b) is almost entirely equivalent to that described in the above patent and consists in the amidation of compound (VIII) with isoserinol.

The reaction was carried out under melting conditions (ie in 120% isoserinol in excess), at a temperature of 90-95oC, for about 12 hours, with the removal of the formed n-butanol by distillation under vacuum. When a butanol solution of compound (VIII) is used, the solution is removed before the reaction to give compound (VIII) as a precipitate, which is finally added with isoserinol. At the end of the reaction, the mass is taken up with water to obtain an aqueous solution of compound (III), in the form of phenol, which is purified from excess isoserinol through a cation exchange resin. The liquids are finally concentrated and the pH is adjusted to 9-10 by adding sodium hydroxide to obtain an aqueous solution of the sodium salt corresponding to compound (III).

The excess isoserinol is recovered in a convenient way and recycled by the dissolution process from the resin with a dilute ammonia solution. The solution is concentrated to a precipitate and then purified by the formation of isoserinol oxalate in an ethanol solution, as described in Italian patent application MI 97 A 000782. The salt is filtered and then dissolved in water. The solution is purified through a strongly acidic polystyrene matrix of cation exchange resin and the isoserinol is recovered by dissolution with dilute ammonia solution. The solution containing the recovered isoserinol is concentrated to a precipitate.

Alternatively, step b) can be carried out without recovering the butyl diester obtained in step a). In this case, at the end of the amidation reaction of compound (VIII) with isoserinol, after dilution with water, the reaction mixture was purified from excess isoserinol by chromatography on a first column containing a strongly acidic cation exchanger and from anionic impurities by chromatography on a second column that contained a weakly basic anion exchanger, connected in series with the first column. A strongly acidic cation exchange resin was selected from those that were commercially available, such as Rohm & Hass Amberjetâ 1200H and a weak base anion exchanger such as Diaion Reliteâ MG1.

Iodination was performed using ICl as an iodizing agent (44.5% I2 in HCl solution) in an aqueous neutral medium in a very narrow pH range of 6 to 7, by adding dibasic sodium phosphate or CaCO3 in excess, at room temperature. In fact, it was observed that at pH >7 Smiles rearrangements, which are characteristic of step e), already take place, and therefore the final compound (I) is partially formed. However, it is convenient to use the ability of compound (VII) to crystallize from water at that step in order to successfully remove all impurities from the previous synthetic steps.

One of the most important aspects of the invention is the control of the amount of iodizing agent, which is obtained in an innovative way and is particularly easy to use even in an industrial destroyer, by means of a potentiometer. Under these conditions, the excess of oxidant can be minimized (up to about 1%), thus avoiding unwanted oxidation side reactions.

It is necessary that the iodizing agent be almost entirely equivalent to the stoichiometric amount or a slight excess (about 1%), and the excess is then destroyed with sodium bisulphite. The resulting solution is directly subjected to alkylation step d), thus avoiding the step using amido derivatives obtained by nucleophilic substitution on the free phenol group of compound (IV), instead of ester derivatives, as disclosed in EP 185,130.

In particular, taking into account the technical instructions of US 5,763,663, the whole synthesis can be shortened by one step. The said patent, in fact, discloses the direct reaction of a phenol precursor with a reactive compound, which already contains the desired amido group. The mentioned patent, of course, only describes the use of a procedure for preparing intermediates for the synthesis of S-N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4, 6-triiodo-1,3-benzenedicarboxamide, known under the commercial name Iopamidol. The mentioned intermediate is, of course, useless for the preparation of Iomeprol, which is the object of the subject invention.

Alkylation of compound (IV) with compound (IX) takes place at a pH of about 6 at a temperature of 95oC, while the alkylating agent is added in amounts of 1.8-2.2 moles per mole of substrate. At the end of the reaction, which usually takes 7 hours, the resulting suspension is cooled and included in the isolation step of compound (VII).

Alternatively, the iodination reaction can be performed without buffer, maintaining the pH at the desired values (between 6 and 7) by adding NaOH.

In this case, the alkylation of compound (IV) with compound (IX) is also carried out by maintaining the pH at about 6 by adding sodium hydroxide, at a temperature of 95oC.

Alkylating agent (IX) is prepared by direct reaction of ethyl chloroacetate and methylamine (40% aqueous solution), which is added to ethyl chloroacetate maintaining the temperature from –10oC to 0oC. Methylamine is added in a slight excess (5-15%). The reaction usually requires 30 minutes; at the end, the mixture is diluted with water and the pH is adjusted to acidic values (between 2 and 5). The resulting aqueous solution of compound (IX) has a concentration of about 30% w/w and can be used directly in the alkylation step.

Step e) can be conventionally performed under the conditions disclosed in EP 365,541.

It is particularly preferred to purify the final solution according to the procedure described in WO 97/30788 using special devices designed to regenerate mixed beads of ion exchange resins, including cation exchange resins and anion exchange resins. Alternatively, the final purification of compound (I) can be carried out according to the procedure described in WO 98/56504, example 5.

Moreover, at the end of the rearrangement, the pH of the solution can be adjusted to 5.5 by removing the sodium hydroxide present using weakly acidic cation resins, instead of adding hydrochloric acid. The preparation is detailed in the experimental section.

The following example illustrates the best experimental conditions to carry out the process of the invention.

Experimental deo

First 1

Preparation of compound (VII) N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[2-(methylamino)-2-oxoethoxy]-1,3-benzenedicarboxamide

A. Preparation of 5-hydroxy-1,3-benzenedicarboxylic acid butyl diester

The esterification reactor is charged under nitrogen with 101.7 kg of n-butanol and 62 kg (320 moles) of 5-hydroxy-1,3-benzenedicarboxylic acid. 2 kg of concentrated sulfuric acid is added with stirring. The resulting suspension is heated until the solvent boils, removing water by azeotropic distillation: about 1.5 hours after the start of heating, a clear solution is obtained, which is heated for an additional 3 hours. After completion of the reaction, the solution is cooled to about 50oC and concentrated under vacuum to obtain the desired product as a molten precipitate. Keeping the temperature of the precipitate above 70oC, a 0.15M NaOH solution is dropped in, to obtain an emulsion of the molten final compound dispersed in water, the pH of which is adjusted to 8.5 with 0.15M NaOH. The emulsion was cooled to 43°C with vigorous stirring, seeded with 1 kg (3.3 mol) of the final compound crystallized from water and cooled slowly to 28°C. The resulting suspension is cooled to 17oC and then filter-pressed, washing the solid part with water until neutral.

The wet product is directly redissolved in a filter press with n-butanol. A solution weighing about 280 kg is obtained, containing 96-97 kg (326-330 moles) of the desired compound.

Yield: 95-96%

B. Preparation of N,N'-bis-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide

Condensation between 41.6 kg (141.3 moles) of the compound prepared in step A) and 56.8 kg (623.4 moles) of isoserinol is carried out in a reactor equipped with a stirrer, at a temperature of about 90-95oC. When the reaction is complete, the final solution is diluted with water and purified through a matrix of strongly acidic polystyrene ion exchange resin, to remove excess isoserinol, by dissolving it with water. The solution from the column is concentrated to standard volume, then alkynized with sodium hydroxide solution, which is added to give a solution of the corresponding sodium salt.

Accordingly, 227.5 kg of a 20% solution containing 45.4 kg (138.6 moles in the form of phenol) of the desired compound is obtained.

Yield 97.9%.

HPLC test: >98% (range)

Isoserinol is easily recovered by dissolving it from the resin with diluted ammonia solution. The solution is concentrated to a precipitate and then purified. Isoserinol is salified with oxalic acid in ethanol solution. The salt is filtered and then dissolved in water. The solution is purified through a strongly acidic matrix of polystyrene ion exchange cation resin and isoserinol is recovered by dissolution with dilute ammonia solution. The solution containing the recovered isoserinol is concentrated to a precipitate.

Yield 76.3%.

C. Preparation of 2-chloro-N-methyl-acetamide

Condensation of 34.5 kg (283 moles) of ethyl chloroacetate and 24 kg (310 moles) of monomethylamine (40% aqueous solution) is performed in a reactor at a temperature of -5oC. After the addition is complete, the solution is kept at a constant temperature for an additional 30 minutes, then it is diluted with 40.5 kg of water and the pH is adjusted to acidic values (pH< 5), to obtain a 30% aqueous solution (99 kg) containing 29.7 kg (276.2 moles) of 2-chloro-N-methylacetamide.

Yield: 98%

D. Preparation of N-N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[2-(methylamino)-2-oxoethoxy]-1,3-benzenedarboxamide

227.5 kg of solution (corresponding to 45.5 kg of dry product in the form of phenol; 138.6 moles) obtained in step B) is diluted with 50 kg of water and added with 10 kg of anhydrous dibasic sodium phosphate. Simultaneously ICl (44.5% aqueous solution of I2) and 30% sodium hydroxide solution are added, maintaining the pH at 7. The addition is completed when the redox potential stabilizes at 500 mV. In total, 120 kg of ICl and 107 kg of sodium hydroxide are charged.

After that 2.5 kg of sodium bisulphite is added to destroy the excess iodine and to reduce the potential to 20 mV.

18.5 kg of anhydrous dibasic sodium phosphate and 99 kg of the 2-chloro-N-methyl-acetamide solution (276.2 mol) prepared in step C are added, the pH is adjusted to 6.2 by adding 3 kg of HCl. The mixture is heated to 95oC and stirred for 7 hours, then cooled to 60oC and diluted with 50 kg of water. The final suspension is again filter-pressed, with the solid part being washed with water.

Accordingly, 130 kg of the desired wet product equivalent to 90 kg of dry product (115.8 moles) is obtained.

Yield: 83.6%

E. Preparation of compound (I)

90 kg of the compound prepared in step D) is suspended in 400 L of deionized water and refluxed. The suspension is added with 310 g of 30% (w/w) sodium hydroxide, then heated to 120oC under pressure, maintaining that temperature for one hour. The mixture is cooled to 50oC, added with 7.7 kg of 30% (w/w) sodium hydroxide and then gradually cooled to 40oC over 2 hours. After an additional 4 hours at 40oC, the mixture is cooled to 20oC and the pH is adjusted to 5.5 with hydrochloric acid. The resulting solution was filled into 160 L of R&H Amberlite 1600 absorbent resin, filling the liquid into a nanofiltration unit equipped with a Desal DK4040 membrane. After filling, dissolve with 800 L of water at 40oC, and collect the solution again in the nanofiltration unit of the tank. During the dissolution or at the end, the nanofiltration unit works until the volume of the solution in the unit is reduced to about 200 L. In this way, the concentration and elimination of most of the sodium chloride contained in the diluted solution is achieved.

The resulting solution of N,N'-bis(2,3-dihydroxypropyl)-5-[(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarboxamide, which will be referred to as solution A, contains 80 kg of the desired product, about 0.05 mol/L of organic ionic impurities (carboxylic aromatic acids) and 0.03 mol of inorganic salts (mainly NaCl).

200 kg of 40% (w/w) solution A is charged at a flow rate of 40 L/h into the unit described in Example WO 97/30788, filled with the same amounts of the same ion exchangers, previously regenerated according to the same method as in this example.

The dilution device is equipped with a conductivity analyzer and a photometer for measuring absorbance at 280 nm, in order to detect the presence of an organic product in the solution. The solution is discarded until the absorbance of the solution begins to rise rapidly, indicating the presence of a concentrated organic product.

From then on, the solution is collected in the tank until solution A is exhausted. During recovery of that fraction, which contains most of the organic product, the conductivity remains below 0.1 mS/cm.

When solution A is exhausted, the mixed base is washed with 30 L of water at the same flow rate and finally again with 150 L of water at a flow rate of 100 L/h, always collecting the solution in the same production fractionation tank.

During this step, the conductivity of the solution is also very low, except for a slight conductivity peak, with a maximum at 20 mS/cm, at the end of the low flow rate wash, probably due to osmotic effects immediately after the product peak.

The fraction corresponding to the desalinated product, which is freed from chlorine ions and carboxylic acids, is thermally concentrated into a thin precipitate containing 15% water. The product is then recovered in almost completely pure form by adding absolute ethanol at reflux temperature, cooling and filtration.

First 2

Alternative preparation of compound (VII)

A. Preparation of 5-hydroxy-1,3-benzenedicarboxylic acid butyl diester

920 g of n-butanol and 583 g of 5-hydroxy-1,3-benzenedicarboxylic acid were charged to an esterification reactor under nitrogen. 32 g of p-toluenesulfonic acid monohydrate is added with stirring. The resulting suspension is heated to solvent reflux, the pressure is gradually reduced to 350 mbar to maintain the temperature of the reaction mixture at 93 to 97oC. These conditions are maintained for 7 hours by removing the formed water through azeotropic distillation. After the completion of the reaction, the solution is cooled to 50oC.

B. Preparation of N,N'-bis-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide

The solution of the compound prepared in step A) is added with 1305 g of isoserinol, the pressure is reduced to 240 mbar, it is heated to 95oC. The reaction is prolonged for 12 hours, with a gradual lowering of the pressure to 30 mbar.

After the completion of the reaction, the final solution is diluted with about 2800 g of water and purified through two columns connected in series containing, respectively, a strongly acidic ion exchange resin to remove excess isoserinol and a weak base ion exchange resin to remove anionic impurities. The product is diluted with water.

The column solution is concentrated to standard volume. Sodium hydroxide is added to obtain a solution of the corresponding sodium salt.

Accordingly, 4200 g of a 25% solution containing 1051 g of the desired compound is obtained.

Isoserinol is recovered from the cationic resin as described in Example 1.

C. Preparation of 2-chloro-N-methyl-acetamide

Condensation between 784 g (6.4 moles) of ethyl chloroacetate and 549 g (7.1 moles) of monomethylamine (40% aqueous solution) is carried out in a reactor kept at -5oC. After completing the addition of amine, the mentioned temperature is maintained for another 30 minutes.

The mixture was diluted with 957 g of water and the pH was adjusted to acidic values (3.5 <pH< 5). The solution is then thermally concentrated under reduced pressure to a precipitate of about 1100 g. The weight is compensated by adding 1570 g of demineralized water to give 1970 g of a 30% aqueous solution containing 674 g of 2-chloro-N-methylacetamide.

D. Preparation of N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[2-(methylanino)-2-oxoethoxy]-1,3-benzenedicarboxamide.

4200 g of the solution of N,N'-bis-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide obtained in step B) is added simultaneously with ICl (keeping the temperature below 25oC) and 30% sodium hydroxide to pH 7 is maintained. Addition of ICl ends when the redox potential stabilizes at 500 mV. A total of 5320 g of ICl and 2580 g of sodium hydroxide are charged. After that, 10 g of sodium bisulfite is introduced to destroy the excess iodine and to reduce the potential to -20 mV.

The resulting solution is then added with 1970 g of the 2-chloro-N-methylacetamide solution obtained in step C). The mixture is heated to 95°C for 7 hours and the pH is maintained at 5.8 by adding 30% sodium hydroxide. After cooling to 30-40oC, the suspension is filtered and the solid part is washed with water.

Therefore, 3350 g of wet product containing 2025 g of the desired product is obtained.

Yield of 5-hydroxy-1,3-benzenedicarboxylic acid: 81.2%

E. Preparation of compound (I)

2000 g of the compound prepared in step D) is suspended in 8660 L of deionized water and refluxed. The suspension is added with 7 g of 30% w/w sodium hydroxide, then heated to 100oC while maintaining this temperature for 2 hours. The mixture was cooled to 50°C with the addition of 172 g of 30% w/w sodium hydroxide, and gradually to 40°C over 2 hours. After an additional 4 hours at 40oC, the mixture cools down to 20oC.

After completion of the reaction, the solution is recycled to a column containing 1.13 L of weakly acidic cation resin to remove the sodium hydroxide present at the end of the reaction, until pH 5.5. The solution is then introduced into 3.55 L of R&H Amberlite 1600 absorption resin connected in series to a battery of four columns containing the ion exchange resins described in WO 98/56504. The volumes of resins in the four columns are 2 L, 0.7 L, 0.47 L and 0.47 L respectively.

The dissolution of the product from the resins was monitored spectrophotometrically.

As soon as the absorbance starts to increase, the solution is collected in the reactor together with successive water washes of the entire battery of columns.

The purified, desalinated solution was thermally concentrated under reduced pressure to a thin precipitate containing 0.22 parts water per part product (w/w). The precipitate was then added, under reflux, to 5 parts (w/w) of absolute ethanol to recover the product.

Claims (11)

1. The procedure for preparing N,N'-bis[2,3-dihydroxypropyl]-5-[(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarboxamide indicated by the fact that it contains the following steps: a) esterification 5-hydroxy-1,3-benzenedicarboxylic acid with n-butanol and acid catalysis to give 5-hydroxy-1,3-benzenedicarboxylic acid n-butyl diester (VIII); b) amidation of compound (VIII) with excess isoserinol to obtain an aqueous solution of N,N'-bis-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzene-dicarboxamide, which was optionally transformed into the sodium salt (III); c) iodination of the compound ( III) with ICl in stoichiometric amounts or in excess of 1%, to give N,N'-bis-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodo-1,3-benzene -dicarboxamide (IV); d)alkylation of compound (IV) with compound (IX), 2-chloro-N-methyl-acetamide in aqueous solution to give N,N'-bis(2,3-dihydroxypropyl)-2 ,4,6-triiodo-5-[2-(methylamino)-2-oxoethoxy]-1,3-benzene-dicarboxamide (VII), which was used as a wet product; e) Smiles rearrangement of compound (VII) under basic conditions and further purification to obtain Iomeprole (I), according to scheme I. 2. The process according to claim 1, characterized in that a catalytic amount of H2SO4 or p-toluenesulfonic acid equivalent to 6% by mole is used. 3. The process according to claims 1-2, characterized in that the compound (VIII) is obtained again by direct crystallization from the final reaction mixture, which is previously concentrated by cooling. 4. The process according to claims 1-2, characterized in that the compound (VIII) is again obtained by precipitation from an alkaline aqueous solution with the previous removal of organic solvents in a thermal precipitate that is successively treated with an inorganic base or an aqueous ammonia solution and then subjected to controlled cooling to give compound (VIII) as a partially solid crystal. 5. The process according to claim 4, characterized in that the compound (VIII), obtained again as a solid, is re-dissolved in n-butanol to obtain a solution which is used as such in the next step. 6. The process according to claims 1-2, characterized in that the n-butyl diester (VIII) obtained in step (a) is not obtained again and at the end of the amidation reaction of compound (VIII) with isoserinol, the reaction mixture is diluted with water, then it is purified from excess isoserinol through a first column containing a strongly acidic cation exchange resin and from ionic impurities through a second weakly basic anion exchange resin connected in series with the first column. 7. The procedure according to claims 1-4, characterized in that step b) is performed in a molten state in 120% excess isoserinol at a temperature of 90-95oC for 12 hours, the n-butanol formed in the reaction is distilled under vacuum, the mass is treated with water after completion of the reaction, to obtain an aqueous solution which is purified through a cation exchange resin and the pH is adjusted to 9-10 with NaOH to obtain an aqueous solution of the sodium salt corresponding to compound (III). 8. The process according to claim 5, characterized in that before the reaction step (b) the solvent is removed to obtain the compound (VIII) as a precipitate, which is finally treated under the conditions of claim 7. 9. The process according to claims 7-8, characterized in that the excess isoserinol is obtained again and recycled in the process by dissolving it from the resin with a dilute ammonia solution, the solution is concentrated to a precipitate and then purified by the formation of isoserinol oxalate in ethanol solution and further purified through the matrix strongly acidic polystyrene ion exchange cation resins, isoserinol is recovered by dissolution with dilute ammonia solution. 10. The method according to claims 1-9, characterized in that the iodination is carried out using ICl, as an iodizing agent, in a neutral aqueous solution at a pH in the range of 6 to 7, at room temperature, with control using a potentiometer so that the addition of the iodizing agent is equivalent to the stoichiometric amount or a slight excess (1%), to obtain a solution that is directly subjected to the alkylating step that follows. 11. The process according to claims 1-10, characterized in that the alkylation of compound (IV) with compound (IX) is carried out at neutral pH and at a temperature of 95oC, the alkylating agent is added in amounts of 1.8-2.2 moles per mole of substrate, at the end reaction, the resulting suspension is cooled and inserted into the step of recovering compound (VII).